Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the development of unusual tumor-like growths (hamartomas) in a variety of organ systems (Gomez, M. R., Ann. N.Y Acad. Sci. 615:1-7 (1991); Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The development of cortical tubers in the brain (regions of abnormal cortical architecture with distinctive large neuronal cells) causes some of the most problematic clinical manifestations of TSC: mental retardation, epilepsy and abnormal behavioral phenotypes including autism and attention deficit-hyperactive disorder (Hunt, et al., J. Autism. Dev. Disorder 23:323-339 (1993); Smalley, et al, J. Autism. Dev. Disorder 22:339-355 (1992)). Other organ systems commonly involved in TSC include the skin, heart, and kidneys (Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The lesions seen are often pathognomonic of TSC and include facial angiofibromas, subungual fibromas, forehead plaque, Shagreen patches, cardiac rhabdomyomas and renal angiomyolipomas and cysts. Renal cell carcinoma also occurs at higher frequency and at an earlier age of onset in TSC patients than in normal individuals (Bjornsson, et al., Am. J. Path. 149:1201-1208 (1996); Cook, et al., J. Med. Genet. 33:480-484 (1996)). About one-third of TSC cases are familial with the remainder being sporadic, i.e., occurring in the absence of a family history of the disease.
Linkage of TSC to 9q34 was first reported in 1987 and this locus was denoted TSC1 (Fryer, et al., Lancet i:659-661 (1987)). Subsequent studies provided strong evidence for locus heterogeneity and led to the identification of 16p13 (denoted the TSC2 locus) as a second genomic region showing linkage in some TSC families (Kandt, et al., Exp. Neurol, 104:223-228 (1989)). Among families large enough to permit linkage analysis, approximately half show linkage to 9q34 and half to 16p13 (Janssen, et al, Hum. Genet. 94:437-440 (1994)).
The TSC2 gene has been isolated and found to consist of 41 coding exons distributed over 45 kb of genomic DNA. It has a message length of 6 kb and encodes several alternatively spliced transcripts and predicted proteins of 1784-1807 amino acids (Maheshwar, et al., Hum. Mol. Genet. 5:131-137 (1996); Xu, et al., Genomics 27:475-480 (1995)). The occurrence of inactivating germline mutations in TSC2 in patients with tuberous sclerosis and loss of heterozygosity (LOH) at the TSC2 locus in up to 50% of TSC-associated hamartomas support a tumor suppressor function for TSC2 (Carbonara, et al., Cancer 15:18-25 (1996); Sepp, et al., J. Med. Genet. 33:962-964 (1996)).
Although the TSC2 gene has been isolated and characterized, identification of the TSC1 gene on 9q34 has proven difficult for a number of reasons. Conflicting positional information has been generated by the analysis of meiotic recombination events in TSC families; large genomic rearrangements (e.g., translocations involving this region) have not been discovered; and several parts of the region are unstable in multiple cloning vectors. In addition, the region contains a number of different genes, any one of which could potentially be TSC1. The unambiguous identification of the TSC1 gene would represent a significant advance in several different respects. First, assays designed to identify mutations in TSC1 could be used to help diagnose this condition in patients exhibiting clinical manifestations suggesting that they may suffer from tuberous sclerosis. Similarly, such assays could be used to help identify patients likely to develop the disorder or likely to pass it on to their offspring.
Therapeutically, the identification of the TSC1 gene and its product may provide a tool for the treatment of abnormal cellular growth. In the case of tuberous sclerosis patients, the introduction and expression of the normal TSC1 gene in place of mutated counterparts should help to prevent the development of hemartomas associated with the disease. In addition, the ability to inhibit uncontrolled cellular growth suggests that TSC1 and its product may have therapeutic applications for other conditions characterized by neoplastic growth.